This program project's goal is to identify artificial porphyrin drugs possessing high virucidal and bactericidal broad spectrum activity and possessing low toxicity for formulation in topical microbicides for intravaginal use to prevent transmission of STDs. Preliminary data establish several porphyrins to be promising light-independent microbicides active against both viruses and bacteria that are prevalent in STD. This project's main aims are the discovery of peripheral substituents (Aim 1) and metal centers (Aim 2) which enhance activity above that of these promising porphyrins. We will provide analytical/biophysical/ mechanistic support to other projects, including the synthesis of porphyrins needed as analogs useful in providing this support. Artificial porphyrin drugs, designed here as NPs and MNPs, can be based on natural porphyrins but with modifications of side chains or side chain and metal, respectively. The corresponding porphyrins derived totally synthetically and with side chains very different from natural porphyrins are designated SPs and MSPs, respectively. The key Project 2 hypotheses guiding our design and selection of MNPs for further development as broad spectrum bactericidal agents are: "MNPs enter bacteria via heme uptake pathways." and "Resistant strains of bacteria would have, of necessity, reduced iron uptake and thus low virulence." Preliminary results in Project 3 show that some of the same MNPs strongly inhibit infectivity of HSV-2. HIV, the focus of project 4, is inhibited by some NPs but SPs and MSPs are more active. The main Project 3 and 4 hypothesis is "Virucidal porphyrins act by specific molecular interactions with viral proteins essential for infection." Since sexual transmission potentially involves either cell-free or cell- associated virus, several porphyrins, differing in cell penetrations may be needed for the formulation of an effective topical rnicrobicide. Overlapping structural features of porphyrins active as HIV, HSV, and bacterial microbicides afford an efficiency in our synthetic evaluation procedures. A highly desirable, realistic outcome of our research would be the identification of one non-toxic agent with very high HSV/HIV virucidal activity and very high bactericidal activity. Given the preliminary and published activity data, this is a realistic goal and we are optimistic. However, a topical microbicide formulation combining several porphyrins or porphyrins with other classes of promising compounds is a potential future direction.